Kidney cancer is comprised of a wide array of histologically and genetically diverse tumors that arise in the kidney. Several subtypes of RCC, distinguishable by unique clinical and histological features, are now recognized. Additionally, by studying familial forms of RCC and more recently, by large scale genomic analysis, a variety of genetic alterations associated with these unique RCC subtypes have been unearthed. The identification of distinct molecular pathways in individual RCC subtypes has served as the foundation for our approach to the evaluation of individualized, mechanism based treatment strategies for these patients. Papillary RCC, accounting for 10-15% of all kidney cancers, is comprised of a heterogeneous group of malignancies characterized by the presence of papillae on histopathologic evalaution. A major scientific interest within the UOB Molecular Therapeutics program is to better characterize the molecular and mechanistic basis of the various subtypes of papillary RCC. As part of a dedicated translational effort to develop mechanism based therapeutic strategies for papillary RCC, a variety of systemic approaches targeting both conventional oncogenes and altered metabolic pathways are being evaluated. Germline activating mutations in the proto-oncogene MET are the basis for the development of bilateral multifocal type 1 papillary tumors in families with a condition termed Hereditary Papillary Renal Cell Cancer (HPRC). In addition, the MET pathway appears to be activated in a subset of patients with sporadic papillary RCC. To determine the relevance of MET as a valid therapeutic target, we helped design and conduct the first trial of a MET tyrosine kinase inhibitor, foretinib (an agent with additional activity against VEGFR2), in patients with papillary RCC. Data from this proof of concept, multicenter phase 2 trial were recently published in the Journal of Clinical Oncology, and demonstrated the efficacy of this approach in papillary RCC, particularly in patients with germline activating mutations in MET. However, dosing of this agent was limited by toxicity related to VEFGR inhibition and it is unclear if optimal MET inhibition was achieved with this drug. We hypothesized that selective MET inhibitors might provide maximal target inhibition with acceptable toxicity. This hypothesis is being evaluated in a phase 2 trial of INC280, a selective, second generation MET inhibitor. A second well studied biochemical alteration in papillary RCC is the preferential utilization of aerobic glycolysis and activation of an oxidative stress response mechanism, best characterized in tumors from patients with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), who carry germline inactivating mutations in the gene for the Krebs' cycle enzyme fumarate hydratase. A targeted approach to these tumors is being studied in an ongoing phase 2 study of bevacizumab and erlotinib. Interim analyses have shown a high response rate (ORR approximately 65% in those with fumarate hydratase mutations) and durable responses in many patients, including those with some forms of sporadic papillary RCC. Based on the unprecedented efficacy seen in the phase 2 trial of bevacizumab and erlotinib, efforts are afoot to further evaluate this regimen as a feasible and effective standard of care option in patients with familial as well as sporadic forms of papillary RCC. As part of this strategy, we are also attempting to identify molecular markers that may help identify sporadic papillary RCC patients most likely to benefit from this approach. A variety of other approaches are also being investigated in a bid to exploit the dependence of some forms of papillary RCC on aerobic glycolysis; a phase 1/2 trial of vandetanib in combination with metformin in patients with sporadic papillary RCC as well as those with altered Krebs cycle (i.e, those with inactivating FH and SDH mutations) has just been initiated. In addition, we plan to evaluate the efficacy of a novel glutaminase inhibitor, CB-839, in tumors where this enzyme is believed to play a key role in maintaining cellular bioenergetics and macromolecule synthesis. Chromophobe kidney cancer accounts for approximately 5% of all RCC diagnoses. Although the majority of chromophobe tumors arise sporadically, these tumors also occur in patients with the familial kidney cancer syndrome, BHD. Patients with BHD are at risk for the development of bilateral multifocal renal tumors of various histologic subtypes, including chromophobe, mixed chomophobe/oncocytic tumors and clear cell RCC. These tumors are the result of germline inactivating mutations in the FLCN gene, usually accompanied by a second, somatic hit resulting in loss of this gene. Using cell lines derived from BHD-tumors as well as animal models of FLCN deficiency, our group has demonstrated that FLCN loss is associated with activation of mTOR and its downstream effectors. Some sporadic chromophobe RCC tumors, which are indistinguishable histologically from those seen in BHD, are also associated with activation of mTOR, kindling interest in clinical evaluation of inhibitors of this pathway. A phase 2 trial to study the efficacy and tolerability of the mTOR inhibitor everolimus in pateints with BHD-associated renal tumors and in patients with metastatic sporadic chormophobe tumors has just been initiated. Patients with BHD and sporadic chromophobe RCC will be accrued to independent cohorts and will accrue patients in parallel. VHL is a familial cancer syndrome characterized by a propensity for the development of bilateral multifocal clear cell RCC as well as tumors in several other organs. While there is a well-defined surgical standard of care for these patients, particularly in the setting of localized disease, there is clearly a need to explore alternatives which would spare these patients the morbidity associated with repeated surgery. Towards this end, the first clinical trial utilizing systemic therapy directed at VHL patients was initiated in the UOB. This phase 2 trial of the heat shock protein 90 inhibitor, 17 AAG, was designed to treat presurgical patients with localized renal tumors associated with VHL and was developed in collaboration with CTEP and Dr. Len Neckers, whose laboratory work provided the preclinical data supporting the evaluation of this class of agents in clear cell RCC. A subsequent phase 2 study evaluating the efficacy of vandetanib, a dual VEGFR and EGFR inhibitor, was initiated in 2008 and remains the largest trial in VHL patients to date; data from this study suggest that while vandetanib is active, the associated side effects have a significant impact on quality of life of these patients with mostly localized tumors generally amenable to surgical management. A variety of preclinical studies are ongoing to evaluate novel approaches in the various subtypes of RCC and are expected to guide future studies in patients with these malignancies.